Trandsdermal compositions and methods for treatment of fibromyalgia and chronic fatigue syndrome

ABSTRACT

Compositions and methods for alleviating the symptoms associated with chronic fatigue syndrome and fibromyalgia syndrome are provided. The compositions are based on use of a transdermal gel formulation delivery system for androgens, either alone or in combination with other hormones.

BACKGROUND OF THE INVENTION

[0001] The Women's Health Initiative (WHI) clinical trial, whose aim wasto prospectively evaluate the risks and benefits of orally administeredcombination hormone replacement therapy in healthy women using estrogensand medroxyprogesterone acetate, was recently halted (Fletcher, S. W. etal. 2002. J. Amer. Med. Assoc. 288:366-368). The increased risks incoronary heart disease, breast cancer, stroke, and pulmonary embolismoutweighed the increased benefits in colorectal cancer, endometrialcancer, hip fractures and death due to other causes, resulting in asmall but statistically significant increased risk for the global indexof hazard ratios among women taking these hormones. The authors pointedout, however, that their study only evaluated healthy women, not thosewith symptoms of hormone deficiency. Furthermore, other routes ofdelivery, e.g. transdermal systems, need to be studied, since it ispossible that transdermal delivery may increase benefits and/or decreaserisks to these patients. It was noted by the authors of the WHI studythat hormone replacement therapy is still considered to be effective forrelieving perimenopausal symptoms such as hot flashes.

[0002] Most clinical trials evaluating sex hormone replacement therapyhave focused on estrogens and progestins, although testosteronereplacement therapy in women who may be testosterone deficient is nowbeginning to be addressed using transdermal delivery systems, e.g. fordisease states in which there is stress from chronic disease with lossof muscle mass and chronic fatigue, such as wasting syndrome in womenwith AIDS (Miller, K. Et al. 1998. J. Clin. Endocrinol. Metab.83:2717-2725; Javanbakht, M. Et al. 2000. J. Clin. Endocrinol. Metab.85:2395-2401). Testosterone replacement therapy using transdermaldelivery has also been of benefit to men with symptoms of testosteronedeficiency, for example in men with Parkinson's disease (Okun, M. S. etal. 2002. Arch. Neurol. 59:1750-1753). There is accumulating evidencethat the sex hormones, in particular estrogens, progestins and nowtestosterone, are important for subjective feelings of well-being andquality of life, parameters that were not assessed in the Women's HealthInitiative trial.

[0003] U.S. Pat. No. 5,935,949 discloses a method of alleviating thesymptoms of fibromyalgia syndrome and chronic fatigue syndrome whichinvolves oral administration of androgens, such as testosterone, topatients. The idea behind the use of testosterone therapy in thetreatment of such conditions is that muscle pain and chronic fatigue,primary symptoms in women with fibromyalgia syndrome (FMS), relates, atleast in part, to testosterone deficiency, since androgens are known toallow for increased musculature and improvement in fatigue. Indeed, asmall decrease in serum free testosterone concentrations has beendocumented for premenopausal fibromyalgia patients relative to healthyvolunteers, but significance was not achieved for postmenopausal women(Dessein, P. H. et al. 1999. Pain 83:313-319). A relationship betweentestosterone and pain sensation has been previously suggested(Blomqvist, A. 2000. Compar. Neurol. 423:549-551). Accumulating evidencesupports the concept that sex hormones can elevate the pain threshold inan individual, for example, during pregnancy (Gintzler, A. R. 1980.Science 210:193-195), when testosterone concentrations, as well asestrogen and progesterone concentrations, are elevated (Bammann, B. L.et al. 1980. Am. J. Obstet. Gynecol. 137:293-298). The theory thattestosterone can suppress pain is supported by the discovery ofaromatase-positive cells in the spinal cord dorsal horn of highervertebrates (quail), where initial processing of pain sensation occurs(Evard, H. Et al. 2000. J. Compar. Neurol. 423:552-564). The presence ofaromatase, which converts testosterone to 17β-estradiol, is interestingbecause it is known that estrogen can induce the transcription ofopiates in estrogen receptor-positive cells derived from the superficiallayers of the spinal dorsal horn (Amandusson, A. et al. 1996. Neurosci.Lett. 196:25-28; Amandusson, A. et al. 1996. Eur. J. Neurosci.8:2440-2445; Amandusson, A. et al. 1999. Pain 83:243-248), a locationthat is important for the synthesis of endogenous opiates.Administration of estrogen to ovariectomized female rats has beendemonstrated to increase spinal cord enkephalin transcription(Amandusson, A. et al. 1999. Pain 83:243-248), and estrogenreceptor-positive cells co-localize with preproenkephalin mRNA(Amandusson, A. et al. 1996. Eur. J. Neurosci. 8:2440-2445). Theseendogenous opiates act on enkephalinergic neurons to mediate inhibitionof nociceptive relay cells, both in primary afferent fibers as well asin pain-modulating fibers descending from the brainstem (Ma, W. Et al.1997. Neuroscience 77:793-811). Thus, both testosterone and estrogenappear to be important for modulating the sensation of pain. However,the differential importance of androgens versus estrogens in painsensation relative to gender remains poorly understood.

[0004] Testosterone may also act at the level of the brain. Testosteroneconcentrations were dramatically decreased in the brain and spinal cordof rats in response to pain-inducing subcutaneous injections of formalininto the paw. In these animals, the loss of testosterone in the centralnervous system was demonstrated to be due to its metabolism by5α-reductase to dihydrotestosterone (Amini, H. Et al. 2002. Pharmacol.Biochem. Behav. 74:199-204). These authors pointed out thatdihydrotestosterone can be metabolized to 5α-androstane-3α,17β-diol,which is an effective modulator of GABA_(A) receptor complexes in thebrain. GABA_(A) receptors are found throughout the brain, and actions ofGABA_(A) receptor modulators in the limbic system, specifically in theamygdala, are associated with feelings of fear. The GABA_(A) receptorion channel complex is one of the most important inhibitory ion channelsin the brain. Thus, testosterone may be important not only formodulation of pain but also for feelings of emotional well-being viabinding of its metabolites to the neurosteroid site of the GABA_(A)receptor, although this remains to be demonstrated.

[0005] Other hormones such as growth hormone may also play a role in thepathogenesis and symptoms of fibromyalgia and chronic fatigue. Forexample, studies have shown that fibromyalgia patients fail to exhibit aproper growth hormone response to acute exercise, a response that islikely related to increased levels of somatostatin a powerful inhibitorof growth hormone synthesis (Crofford, L. J. et al. 2002. Arthr.Rheumat. 46:1136-1138; Paiva, E. S. et al. 2002. Arthr. Rheumat.46:1344-1350). It is well known that testosterone increases growthhormone secretion. Growth hormone secretion is reduced in senescencebeyond the reduced levels of secretion seen in adult life after puberty.This reduction is thought to relate to the decreased lean body mass toadipose mass ratio known to occur in some individuals in senescence.Thus, increased somatostatin levels may reflect decreased anabolism anddecreased muscle mass due to decreased testosterone and growth hormoneconcentrations in fibromyalgia patients. As a result, therapy withgrowth hormone may improve the condition of patients with fibromyalgia.

[0006] It has now been found that transdermal hormone therapy in womencan raise serum hormone concentrations to levels that approximate thosenormally found in premenopausal women, as well as relieve symptoms inpatients with fibromyalgia.

SUMMARY OF THE INVENTION

[0007] An object of the present invention is a composition forincreasing androgen levels in blood which comprises an androgen at aconcentration of about one percent and a pharmaceutically acceptablegel. The androgen compounds of the instant invention may comprisetestosterone and its derivatives.

[0008] Another object of the present invention is administration of theandrogen gel formulation along with compounds that increase levels ofgrowth hormone in blood, or growth hormone itself.

[0009] Another object of the present invention is a method ofalleviating the symptoms of fibromyalgia syndrome and chronic fatiguesyndrome which comprises administering to a patient suffering fromfibromyalgia syndrome or chronic fatigue syndrome an effective amount ofthe androgen gel formulation so that the symptoms are alleviated. Inother embodiments of this method the administered product can be a gelwith a combination of androgen hormones as well as compounds thatincrease levels of growth hormone in blood. Further, the method of theinvention contemplates administration of the androgen gel formulationand separate injection of growth hormone in the patients.

DESCRIPTION OF THE DRAWINGS

[0010]FIG. 1 depicts the levels of total testosterone in blood of thepatients, an average of the group, over time on day 1 (shown withcircles) and day 28 (shown with squares).

[0011]FIG. 2 depicts the results of the tender point evaluationspre-treatment (day 0) and at the end of the study (day 28). The resultsreported are levels of pain on a scale of 0 (no pain) to 10 (highestlevel of pain).

[0012]FIG. 3 depicts the results of the dolorimetry assessment of tenderpoint pain pre-treatment (day 0) and at the end of the study (day 28).

[0013]FIG. 4 depicts the severity of symptoms/conditions associated withfibromyalgia and chronic fatigue on a scale of 1 to 10 (10 being thehighest increased level) on day 1 versus day 28 of the study. Thesymptoms/conditions assessed included libido, muscle pain, tiredness,headache severity, headache Frequency, stiffness, sleeplessness, fatigueupon awakening, anxiety, and depression.

DETAILED DESCRIPTION OF THE INVENTION

[0014] The syndrome of chronic fatigue has received much attentionlately. No physical finding or laboratory test can be used to confirmdiagnosis of chronic fatigue syndrome. However, this syndrome isgenerally characterized by fatigue persisting or relapsing for more thansix months occurring concurrently with at least four or more of thefollowing symptoms: impaired memory or concentration, sore throat,tender cervical or axillary lymph nodes, muscle pain, multi-joint pain,new headaches, unrefreshing sleep, and post exertion malaise. Earlystudies suggested an infectious or immune dysregulation mechanism forthe pathophysiology of chronic fatigue syndrome. More recent studieshave shown that neurologic, affective and cognitive symptoms alsofrequently occur.

[0015] Fibromyalgia (also referred to as fibrositis) is one of the mostcommon rheumatic syndromes in ambulatory general medicine affecting3-10% of the general population. Most patients with FibromyalgiaSyndrome (FMS) are women, and of these patients, approximately 50-75%are women in their peri-postmenopausal years, aged 40-60. Approximately2-5% of peri/post menopausal women are affected by FMS, with someestimates ranging from 0.5 to 20%. This disease is characterized bychronic widespread musculoskeletal pain syndrome with multiple tenderpoints, fatigue, headaches, lack of restorative sleep and numbness.Fibromyalgia shares many features with chronic fatigue syndromeincluding an increased frequency in peri/post menopausal woman, absenceof objective findings and absence of diagnostic laboratory tests.Further, these conditions have overlapping clinical features includingchronic fatigue, headaches and lack of restorative sleep withmusculoskeletal pain predominating in fibromyalgia and apparentincreased susceptibility or hyperimmunologic responsiveness to infectionpredominating in chronic fatigue syndrome.

[0016] Various treatments for chronic fatigue syndrome includingacyclovir, oral and vaginal nystatin and fluoxetine have been tried withlittle success. Placebo-controlled trials have demonstrated modestefficacy of amitriptyline, fluoxetine, chlorpromazine, orcyclobenzaprine in treating fibromyalgia. Exercise programs have alsobeen suggested as beneficial in both conditions. Accordingly, there isclearly a need for better treatments for these debilitating conditions.

[0017] It has now been found that transdermal administration ofhormones, including androgens, can alleviate symptoms in patientssuffering from FMS or CFS. By “androgen therapy” it is meant to includeadministration of a single androgen or a combination of androgens. By“alleviate” it is meant to make less hard to bear, reduce or decrease,or lighten or relieve patients of the symptoms of FMS of CFS. By“symptoms” of FMS or CFS it is meant to include muscle pain and atrophy,chronic fatigue, lack of restorative sleep, increased susceptibility toinfection and headaches resulting from FMS or CFS.

[0018] A clinical trial was performed to investigate thepharmacokinetics and efficacy of transdermal delivery of hormones fortreatment of fibromyalgia. Women were recruited by institutional reviewboard-approved advertising. Subjects aged 40-55 and diagnosed forfibromyalgia using American College of Rheumatology criteria ({fraction(11/18)} bilateral tender points above and below the waist, chronicfatigue, etc., (Wolfe, F. et al. 1990. Arthrit. Rheumat. 33:160-172)were selected for the study if they fit additional criteria. Women wereincluded if, in addition to meeting all other criteria, they agreed tokeep their medicines unchanged during the study (decreases in analgesicswere permitted). Women taking hormone replacement therapy were enrolledif they agreed to come off hormone therapy at least 2 weeks prior to,and for the duration of, the study, in addition to meeting othereligibility criteria. Pre- or peri-menopausal women were required tohave adequate alternative contraception, a negative pregnancy test, andtreatment was started within the follicular (proliferative) phase of themenstrual cycle. Patients were included if they were willing to exercise20 minutes a day, 5 days per week during therapy, to promote the effectsof testosterone; this was a requirement put in place by theInstitutional Review Board.

[0019] Children, pregnant women, and women on hormone therapy, hormonecontraceptives or infertility drugs were excluded. Women were excludedfrom the study if they reported undiagnosed vaginal bleeding, had a bodymass index BMI >30, admitted to ethanol or illicit drug abuse, hadactive thrombophlebitis, breast cancer, hypertension (BP>160 systolic/95diastolic with or without medication, after sitting 5 minutes), or majorskin disease, acne or hirsutism. Prior to enrollment, study patientblood was tested for the following general health criteria (exclusioncriteria in parentheses): cardiac risk factors by lipid profile—totalfasting cholesterol (>240 mg/dL), high density lipoprotein (<35 mg/dL),low density lipoprotein (>210 mg/dL), triglyceride (>300 mg/L); hepaticfunction by alanine aminotransferase (>1.5×N, normal at 0-40 U/L),alkaline phosphatase (>2×N, normal at 40-120 U/L), aspartateaminotransferase (>1.5×N, normal at 10-30 U/L), serum albumin (>N,normal at 3.2-5.2 g/dL), total bilirubin (>N, normal at 0.2-1.3 mg/dL),and direct (conjugated, soluble) bilirubin (>N, normal at 0.0-0.3mg/dL); kidney function by blood urea nitrogen (>2×N, normal at 8-18mg/dL) and serum creatinine (>N, normal at 0.7-1.2 mg/dL) tests;hematological function was assessed by complete blood cell countincluding testing for hemoglobin (normal, 12-16 g/dL). Blood tests andphysical exam at the end of the study were performed to assess whethertestosterone therapy adversely affected the general health of the studypatient. Serum total testosterone (>0.4 ng/mL) and FSH (<22 IU/L) weretested as well (8 AM after overnight fasting), to confirm patients hadconcentrations of testosterone in the lower half of the reference range(2 patients out of 18 were excluded based on testosteroneconcentrations) and to determine their postmenopausal status. FSHconcentrations <22 IU/L indicated premenopausal or perimenopausal statusand thus the need for adequate contraception, unless the patient hadundergone bilateral oophorectomy. Testosterone serum concentrations weretested at 8 AM due to the small circadian rhythm of circulatingandrogens. The most frequent exclusion criterion was for BMI >30.Patients were required to stop taking St. John's wort, since St. John'swort is known to induce catabolism of hormones by activating CYP3A, adetoxifying enzyme complex in the liver. Twelve patients who fit theeligibility criteria, above, were scheduled for physical exams includingtender point assessment, verification of fibromyalgia diagnosis, andassessment of general health.

[0020] On day 1, blood was drawn by venipuncture at 0, 1, 2, 3, 4, 6, 8,10, 12 and 24 hrs for 24 hr pharmacokinetic profiling of baselinetestosterone serum concentrations. Testosterone gel, 0.75 g 1% w/w, wasapplied by the patient to their lower abdominal skin just after the zerotime point blood draw (8 AM) The patient also filled out a painassessment questionnaire form and was given packets of testosterone gelfor 8:00 AM daily application to lower abdominal skin, instructions foruse and a patient medication log and exercise log for 28 days oftherapy. On day 28, the blood draws for 24 hr pharmacokinetic profilingwere repeated, and a follow-up exam was repeated at the end of the 28days of therapy.

[0021] The delivery vehicle for this study was a gel formulation. It waschosen for use as a goal of the study was to identify a transdermaldelivery system for hormones that would result in effective levels ofhormones in blood as a way to reduce side effects of androgen therapy.The gel used for this study was a 1% w/w testosterone gel, USP grade.The daily gel dose applied was 0.75 grams; an expected bioavailabilityof 10% would deliver 0.75 mg testosterone over 24 hr. The gel wasformulated for women by Bentley Pharmaceuticals, Inc. (North Hampton,N.H.) using good manufacturing practice standards, and is colorless,comfortable on the skin, and non-staining.

[0022] Testosterone concentrations were determined by enzyme linkedimmunoassay (EIA, Diagnostic Systems Laboratories or DSL, Inc, Webster,Tex.), where serum testosterone from study subjects competed withenzyme-linked testosterone bound to anti-testosterone mAb. This assaysystem was designed to detect the lower concentrations of testosteronefound in women as well as concentrations in the upper ranges. Freetestosterone concentrations were determined by EIA using ananti-testosterone antibody that recognizes the unbound testosterone inthe test sample, and has low affinity for sex hormone binding globulinand albumin. For the purposes of determining mean testosteroneconcentrations, times were based on the nearest hour. Of the 240 timepoints taken for the pharmacokinetic data (10 time points perindividual×2 sets per individual×12 individuals), 1 time point wasmissed (#012, 4 hr point) and 3 additional time points were in betweenthe standard times for taking blood (#010, 8 hr point; #012, 4 hr and 10hr points). Values for these time points were derived by interpolationfor the purposes of deriving mean testosterone concentrations. Anoncompartmental pharmacokinetic analysis using WinNonlin Pro(Pharsight, Mountain View, Calif.) used the exact time points recordedfor all the patients

[0023] In order to determine the efficacy of the treatment for reducingsymptoms of fibromyalgia, patients filled out questionnaire forms on day1 and again at the end of therapy on day 28 to assess pain. The patientquestionnaire was based on a published and validated Fibromyalgia ImpactQuestionnaire as well as other accepted criteria for fibromyalgiapatient assessment (Wolfe, F. et al. 1990. Arthrit. Rheumat. 33:160-172; Goldenberg, D. Et al. 1996. Arthrit. Rheumat. 39:1852-1859;Burckhardt, C. S. et al. 1991. J. Rheumatol. 18:728-733), and used a 100mm visual analog scale (VAS). Tender point exams were administered by aqualified rheumatologist experienced in treating women withfibromyalgia, and involved applying approximately 9 pounds of pressureat each tender point and asking whether the patient felt pain. Thispractice is in accordance with criteria specified by the AmericanCollege of Rheumatology. Exams were administered just prior to Day 1 oftherapy (and therefore designated as “pretreatment”), and at the end oftherapy. The pretreatment tender point assessment was performed on allpatients within 1 week before the start of therapy. Dolorimeter readingswere taken from the bilateral second costochondral junction andtrapezium tender points, for comparison, in 11 of the 12 study subjects.

[0024] Pharmacokinetic analysis of serum testosterone concentration datawas carried out using WinNonlin Pro software, using the noncompartmentalmodel with extravascular input. Differences between Day 1 and Day 28maximum plasma concentrations (C_(max)) and area under the curve (AUC)of a plot of plasma concentrations over time were assessed bycalculating individual subject Day 28 minus Day 1 data and estimating95% confidence intervals of this difference to determine if significance(p<0.05) was reached. Tender point data evaluations were analyzed byStudent's t test (paired, 2-tailed).

[0025] Analysis of the blood testosterone concentration data revealedthat serum total testosterone concentrations were reliably increased infibromyalgia patients in response to testosterone gel hormonereplacement therapy. Serum free testosterone concentrations vs time datafor Day 1 and Day 28 are shown in FIG. 1. Comparison of the serumtestosterone data to standard reference ranges for the concentration oftotal testosterone in serum from women confirmed that the fibromyalgiapatients in this study initially had total testosterone concentrationsin the lower half of the reference ranges. However, the mean serumconcentration of total testosterone 24 hr after application of the firstdose of hormone on Day 1 was significantly higher than the mean serumconcentration for time zero on Day 1 (FIG. 1, p=0.01), indicating thatserum concentrations were sustained, on average, early on during the 28day time course. Steady state concentrations were reached by day 28, asevidenced by the similar mean concentrations at the beginning and end ofthe 24 hr sampling (see FIG. 1). There was variation in the 24 hrprofiles for serum testosterone when analyzed on an inter-individualbasis, consistent with the complex regulation known for this hormone.Summary pharmacokinetic parameter analysis demonstrated significantlyincreased mean total testosterone maximum concentration in response totestosterone therapy: C_(max) was 1.92 ng/mL on day 28 compared with1.21 ng/mL on day 1, p<0.05. Significantly increased mean totaltestosterone area under the curve values (assessed over the 24 hrprofiling time period) were also found: AUC was 28.75 ng-h/mL on day 28compared with 18.36 ng-h/mL on day 1, p<0.05. Considered together thepharmacokinetic data demonstrated that with therapy, mean serum totaltestosterone concentrations initially rose quickly over the first 3hours and were then reliably sustained over time. In addition, meanserum concentrations were raised from the lower boundary of thereference range to just above the upper end of the reference range forpremenopausal women.

[0026] Concentrations of free testosterone in serum were also examinedand subjected to pharmacokinetic analysis. Results similar to totaltestosterone results were obtained. However, two of the twelve patientshad unusually high concentrations of free testosterone prior to, andthroughout, the course of therapy. Individual profiles for the remainderof the patients showed concentrations that increased from thepostmenopausal range to the premenopausal and upper postmenopausalreference range. Summary pharmacokinetic parameter analysis showed amean free testosterone C_(max) of 4.69 pg/mL on day 28 compared with3.68 pg/mL on day 1 (p>0.05) and a mean free testosterone AUC of 71.38pg-h/mL on day 28 compared with 54.35 pg-h/mL on day 1 (p>0.05). Freetestosterone C_(max) and AUC were increased with therapy, as evidencedby subtraction of the day 1 baseline from day 28 values, but statisticalsignificance was not achieved in these pharmacokinetic parameters due tothe two individuals with exceptionally high free testosteroneconcentrations. The high concentrations of free testosterone in thosetwo patients contrasted with the normal total testosterone profiles forthese particular individuals, raising the possibility that these highfree hormone concentrations may have resulted from low sex hormonebinding globulin concentrations in their serum, although otherexplanations exist. The only medication or supplement reported by bothof these study subjects, and not used by any other subjects, was gingerroot. (It is not known if ginger root interferes with the enzyme linkedimmunoassay for free testosterone, or with sex hormone binding globulinmetabolic or binding parameters.)

[0027] Analysis of the tender point pain data showed that transdermaltestosterone gel therapy was associated with decreased subjectiveassessments of pain. Using a pain scale of 0 to 10, where zero is nopain, there were mean decreases in pain for every tender point, withstatistical significance achieved in 9 of 18 categories assessed(categories assessed are listed below in Table 1; results shown in FIG.2. Using a dolorimeter to assess pain at the same office visit, painresponses were quantitated for the bilateral second costochondraljunction and bilateral trapezium tender points (FIG. 3). Individualresponse values ranged from 2 to 9. Mean dolorimeter values for thepressure at which patients reported pain were higher at the end of 28days of testosterone treatment, which would be expected if therapyincreased thresholds of pain, although the dolorimetry results did notreach statistical significance. TABLE 1 Tender Points Evaluated TenderTender Lay Point # Point Description Description  1-2 lower bilaterallower cervical at the base cervical (paraspinals) at the anterior of theneck aspect of the intertransverse in the back spaces at C5-7  3-4second rib bilateral at the second on the costochondral junction (rib-breast bone cartilage) just lateral to the junction of the upper surface 5-6 lateral bilateral lateral epicondyle in on the epicondyle forearm,2 cm distal to the outer edge epicondyles of the forearm about an inchbelow the elbow  7-8 gluteal bilateral gluteal in the upper on the outerquadrant of buttock in the outside of anterior fold of muscle the hip 9-10 occiput bilateral occiput at the At the base insertion of thesuboccipital of the muscle skull beside the spinal column 11-12trapezius bilateral trapezius at midpoint on top of of the upper borderthe shoulder toward the back (flat triangular muscle post, neck,shoulder) 13-14 supraspinatus bilateral supraspinatus at its over theorigin above the scapular spine shoulder near the nedial border blade15-16 greater bilateral greater trochanter at the top trochanterposterior to the trochanteric of the hip prominence 17-18 knee bilateralknee at the medial fat on the fat pad just proximal to the joint padover line the knee

[0028] Pain parameters were also evaluated by patient questionnaireusing a visual analog scale (VAS) from 0-10 (FIG. 4). Libido (sex drive)was increased in response to testosterone treatment. Muscle pain,tenderness, stiffness and fatigue upon awakening were all decreasedduring testosterone treatment. These findings are consistent with theidea that restoration of premenopausal serum testosterone concentrationsrelieves symptoms that most specifically relate to testosteronedeficiency, e.g. loss of sexual desire, loss of muscle function andincreased fatigue. Blood tests and physical exam at the end of the studyverified testosterone therapy did not adversely affect the generalhealth of the study patient, and no study patient reported any adverseevents that were attributable to the treatment.

[0029] Most trials involving hormone replacement therapy have usedderivatives of hormones naturally found in women. These derivatizedhormones have been promoted because of their patentability and theirextended half life. Androgens are no exception since the androgenhormone most prescribed for women is methyltestosterone, wheremethylation at the C-17 position increases its oral bioavailability. Asubset of patients do not tolerate derivatized hormones very well,however. Non-derivatized exogenous hormones that are structurallyidentical to endogenous hormones have short plasma/serum half lives thatrange from 10-100 minutes, making oral administration of native hormonesproblematic. Investigators have begun to develop transdermal deliverysystems, which provide sustained delivery while minimizinghepatotoxicity. A testosterone skin patch has been effective in HIVseropositive women with wasting syndrome (Miller, K. et al. 1998. J.Clin. Endocrinol. Metab. 83:2717-2725; Javanbakht, M. et al. 2000. J.Clin. Endocrinol. Metab. 85:2395-2401), but the skin patch causestopical skin irritation in many women, making its use problematic.

[0030] The present invention involves use of a testosterone formulatedas a gel in a concentration that is appropriate for women. The data haveshown this formulation to provide effective systemic delivery oftestosterone in patients with fibromyalgia. 28 days of therapy with 0.75g 1% (w/w) testosterone gel per day raised serum concentrations of totaland free testosterone in fibromyalgia patients to concentrationsapproximating those in premenopausal women. At this dose, patientsshowed significantly decreased muscle pain, decreased stiffness,decreased fatigue and increased libido in response to testosteronetherapy. Tender point pain was decreased, as well. These results, fromboth the pharmacokinetic and pain assessment standpoints, support theuse of testosterone replacement therapy to treat individuals withfibromyalgia syndrome.

[0031] Accordingly, androgen therapy provides a useful means foralleviating symptoms associated with FMS or CFS in women preferably ofperi/post menopausal age. By peri/postmenopausal age it is most oftenmeant to be approximately 40 to 60 years of age. Women outside of thisrange may also benefit since these syndromes have been known to bepresent in women 20 to 60 years of age. In a preferred embodiment, theandrogen administered comprises testosterone, an active metabolite oftestosterone such as dihydrotestosterone or androstenedione or atestosterone derivative such as methyltestosterone, testosteroneenanthate or testosterone cypionate. Examples of available pharmacologicpreparations of androgens believed to be useful in this inventioninclude, but are not limited to danazol, fluoxymesterone, oxandrolone,methyltestosterone, nandrolone decanoate, nandrolone phenpropionate,oxymethalone, stanozolol, methandrostenolone, testolactone, pregnenoloneand dehydroepiandrosterone (DHEA).

[0032] In the present invention, the androgens are administeredtransdermally in a gel formulation. This formulation has advantages overcurrent oral methods as well as transdermal patch methods that includeimproved bioavailability and a low side effect profile. In a preferredembodiment, a combination of androgens such as testosterone or atestosterone derivative and DHEA can be administered to alleviate boththe muscular and neurological symptoms of FMS or CFS.

[0033] As will be obvious to those of skill in the art upon thisdisclosure, other pharmaceutically acceptable androgen therapies can beused. Effective amounts and routes by which the androgen or combinationof androgens can be administered in the present invention can beroutinely determined by those skilled in the art in accordance withother uses for androgen therapies.

[0034] The composition of the present invention comprises, in additionto the aforementioned androgen/anabolic agent, co-treatment with apharmaceutically effective amount of growth hormone elicitor oreffector, either growth hormone or an agent that is known to releasegrowth hormone in effective amounts, i.e., a growth hormone releasingagent (“GRF”). GRF is an acronym based on the existence of an endogenoushormone known as GHRH. Other agents include GHrelin or a growth hormonereleasing peptide or analog (GHRP; GHRP-6, or hexarelin,His-DTrp-Ala-Trp-DPhe-Lys, and GHRP-2, or Dala-D-2-NaI-Ala-Trp-Dphe-Lysare examples), which have been shown to release effective amounts ofgrowth hormone. The natural rhythm of growth hormone release from thepituitary gland results in release of insulin-like growth factor(IGF-1), which in general, is considered to be the causal agent thatdetermines the course of hormonal regulation and balance in processessuch as adipogenesis and myogenesis. The hormonal effector, then, forthe purpose of this invention, is also prophetically considered to beany peptide or peptidomimetic agent that directly acts to release thissecondary anabolic growth factor, (IGF-1), not necessarily through theintermediary route of secretion of growth hormone itself. Although theindirect growth hormone route is preferred to elicit IGF-1, the latterroute to directly release IGF-1 also is included by example.

[0035] In another embodiment of the present invention, the compositioncomprises a pharmaceutically effective amount of a growth hormone or,more preferably, a growth hormone-releasing agent, or an elicitor ofIGF-1 secretion, coupled with androgen treatment and such combinedtreatment being capable of counteracting the deleterious effects ofaging, such as, for example, muscle weakness, body fat increases, andskin fragility in adults. Essentially any suitable growthhormone-releasing agent may be employed in combination with anyandrogen, preferably one such as testosterone that possesses stronganabolic activity. Other anabolic agents that are not thought of asandrogenic agents, or do not possess maximal androgenic activity may beused, as long as they have appreciable anabolic activity. In fact, thisinvention anticipates, and includes as a prophetic example, thoseanabolic agents that may be completely devoid of androgenic activity.Examples of such growth hormone-releasing agents include:somatoliberins; growth hormone-releasing hormone active fragments, suchas, for example, hGRF (1-29) amide and hexarelin (GHRP-6). Hexarelin isa growth hormone releasing peptide mimetic agent, i.e., it mimics theeffects of growth hormone releasing peptide in the body and containsbetween 2 and 20 amino acids. In particularly preferred embodiments,more than one growth hormone-releasing agent may be used in combination.A preferred combination comprises growth hormone-releasing factor (GRFor GHRH) and a growth hormone releasing peptide or peptidomimetic(GHRP). This combination has been reported to act by separate mechanismsfor the release of endogenous growth hormone, and the effects have beenshown in some cases to be additive, or even, synergistic, working at aseparate receptor often called the Ghrelin receptor, to differentiate itfrom the GHRH receptor. Since the GHrelin receptor has recently beenelucidated, prophetically other ligands for this receptor areanticipated to be synthesized and/or discovered in the future, and theseare included by example (Baldelli, R et. al. Endocrine 14 (1):95-99,2001). These are often referred to as GHSs (growth hormonesecretagogue).

[0036] The administration of a GH or IGF-1 secretagogue will reduceplasma androgen concentration in humans (Tapanainem J et. al, Fertilityand Sterility 58: 726-732). This effect increases the need for exogenousandrogen, such as testosterone, to be also administered as aco-treatment to restore and amplify existing levels.

[0037] Other compounds are known to affect this system which is known asthe hypothalamo-pituitary-hepatic axis for GH, among other terms.Prophetically, it is probable that other compounds involved in thishormonal regulatory system may play a role in indirectly or directlyinfluencing and increasing levels of GH, IGF-1, or IGF-2, and may beadministered in the context of this invention along with the androgenicsupplementation to get maximal effects of the growth/anti-aging effectsof such treatment. Other indications that may be treated besidesfibromyalgia may be syndromes affecting the growth of individuals,including but not limited to pituitary dwarfism, conditions or syndromesthat are well known to practitioners in the field of endocrinology,growth, and aging.

[0038] For the administration of the GH agents that are described indetail above, they may be administered by a variety of means. Theseagents may be administered separately from the androgen administration,using the modalities of intranasal, transdermal, parenteral(subcutaneous or intravenous), or oral (with or without permeationenhancement and preferably with enteric protection, since proteins andpeptides may be degraded by gastric exposure). GH itself is mostpreferably administered by parenteral means in practice, because it is alarge protein that is of limited stability and limited absorption.However, intranasal administration is also an acceptable means for thisand other large proteins or peptides. After the administration modalityis chosen for the GH agent, the androgen may be administered in aseparate treatment with a different regimen. The desired method forandrogen administration is preferably oral, transdermal, intravaginal,or intranasal delivery, although it is most preferred to be administeredtransdermally in the form of a gel or patch. The literature is repletewith examples of compositions suitable in the context of this disclosurefor the transdermal administration of these compounds in solution, gel,emulsion, or patch forms.

[0039] In addition to a separate delivery modality for the GH agent andthe androgenic compound selected for treatment, the two may be combinedin a single combination therapy. For example, both could be incorporatedtogether in an oral form, tablet, or suspension, with the caveat thatany proteinaceous agent is suitably protected from gastric degradation.Alternatively, the combination of agents may be administeredintranasally in one unit through separate delivery chambers, known tothose of skill in intranasal delivery, or together in the same liquid,semi-solid, or solid delivery form. For example, a microparticulate ornanoparticulate dry solid system could be administered intranasally. Orthe combined agents could-be both administered transdermally. The twotreatments could be incorporated together in a patch, or most preferablyin a topical liquid or semi-solid (gel) delivery system. This lattermethod is most effectively realized in practice for GH agents of thesecretagogue (GHSs) variety, such as GHRPs or GHRHs or suitable GHRHfragments that still retain the necessary GH releasing activity. Thereason for the suitability is based on the molecular size. It is knownthroughout the literature that smaller molecules have a higher potentialfor transdermal delivery than large molecules, such as oligopeptidesincluding GH and IGF-1. The GHrelins and GHRH secretagogues are mostpreferably selected for the transdermal route based upon small molecularsize, such as hexarelin, since transdermal delivery efficiency is goodfor a hexapeptide. In general, it is preferred that peptides below 30amino acids are considered for the transdermal delivery format.

[0040] Additional clinical studies to confirm the ability of androgentherapy combined with these other hormones to alleviate the symptoms ofFMS will be performed. In these studies, the ability of the combinedtherapy to resolve muscle pain in peri/postmenopausal women diagnosedwith FMS will be evaluated. More specifically, patients will be examinedfor an inverse correlation between serum hormone levels and diminishmentin muscle pain. The study will be designed to be similar to the studydiscussed above in this application. Patients will be assigned randomlyto one of the following regimens: 1) placebo twice a day for two months;2) combination testosterone therapy comprising testosterone and thehormone for testing (e.g., growth hormone) for two months; 3)testosterone for 2 months; or 4) test hormone for two months. Thesetreatments will be followed by a one month washout phase and thepatients will again be randomly assigned to one of the above treatmentregimens for another two month period.

[0041] Patients will be provided with a Patient Questionnaire Form tofill out to assess their symptoms and level of pain in asemi-quantitative manner at the baseline, 2 month and 5 monthtimepoints. Included in the questionnaire are parameters for patients toevaluate that are common to published and validated FMS patientquestionnaires such as sleeplessness, fatigue, headache and stiffness(Wolfe et al., Arthritis and Rheumatism, 1990, 33(2):160-172; Goldenberget al., Arthritis and Rheumatism, 1996, 39(11):1852-9; and Burckhardt etal., J. Rheumatology, 1991, 18:728-33). The attending physician willalso complete a Physician's Form at the baseline, 2 month and 5 monthtime points to verify that the patient fulfills the criteria for FMS bythe American College of Rheumatology, and to document the intensity ofthe muscle pain for each of the 18 commonly recognized tender pointsthat patients with FMS are known to have.

[0042] Patients will be tested at the baseline, 2 month and 5 month timepoints for total serum hormone levels, serum estradiol levels, cardiachealth and liver function. Patients will be tested at a common time ofday, preferably a predetermined peak time for the androgen, afterfasting since midnight, and on day 3 after the start of their menstrualperiod if they are still menstruating.

What is claimed is:
 1. A composition for increasing androgen levels inblood comprising an androgen at a concentration of about one percent anda pharmaceutically acceptable gel.
 2. The composition of claim 1 whereinsaid androgen comprises testosterone, a testosterone derivative or acombination of testosterone and a testosterone derivative.
 3. Thecomposition of claim 1 further comprising a compound that increaseslevels of growth hormone or IGF-I in blood.
 4. A method of alleviatingthe symptoms of fibromyalgia syndrome and chronic fatigue syndromecomprising administering to a patient suffering fibromyalgia syndrome orchronic fatigue syndrome an effective amount of the composition of claim1 so that the symptoms are alleviated.
 5. The method of claim 4 whereinthe patient is a female of peri/postmenstrual age.
 6. The method ofclaim 4 wherein the androgen comprises a testosterone derivative.
 7. Themethod of claim 4 wherein a combination of androgens is administered tothe patient.
 8. The method of claim 7 wherein the combination ofandrogens comprises testosterone or a testosterone derivative anddehydroepiandrosterone.
 9. The method of claim 4 wherein a combinationof an androgen and a growth hormone is administered to the patient. 10.The method of claim 4 wherein a combination of an androgen and acompound that increases levels of growth hormone in blood isadministered to the patient.
 11. The method of claim 10 wherein thecompound is selected from the group consisting of growth hormonereleasing peptides, growth hormone releasing hormone, IGF-1, and IGF-2.12. The method of claim 10 wherein the compound is selected from thegroup consisting of growth hormone and derivatives thereof, IGF-1 andIGF-2, or derivatives thereof.
 13. The method of claim 11 wherein thecompound is a growth hormone releasing peptide mimetic compound that isbetween 2 and 20 amino acids in length and is known to release growthhormone.
 14. The method of claim 13 wherein the growth hormone releasingpeptide mimetic is hexarelin.